Targeting HPK1 for cancer immunotherapy: An update on recent medicinal chemistry advances

Hematopoietic progenitor kinase 1 (HPK1), a pivotal negative regulator of immune signaling pathways, represents an attractive therapeutic target for cancer immunotherapy. Supported by encouraging preliminary clinical data showing promising efficacy and manageable safety profiles in clinical trials, the rapid development of structurally diverse small-molecule HPK1 inhibitors continues. However, achieving high selectivity for HPK1 remains challenging due to significant sequence homology among the related kinase family. Emerging evidence also implicates HPK1's non-catalytic scaffolding function in tumor immune regulation, complicating traditional inhibition strategies. Notably, PROteolysis-TArgeting Chimeras (PROTAC) technology offers distinct advantages for targeting HPK1, driving significant momentum in the development of novel HPK1 PROTACs. This article provides a comprehensive update on recent advances in HPK1-targeted therapeutics, highlighting key progress in the evolution of structurally distinct small-molecule HPK1 inhibitors with improved selectivity, ADME and safety profiles, the development and pharmacological outcomes of HPK1-targeted PROTACs, as well as translational progress of clinical-stage candidates. Finally, we discuss future perspectives and challenges in this rapidly evolving field.